S169: MODULATION OF THE IMMUNE LANDSCAPE IN LOWER-RISK MYELODYSPLASTIC SYNDROMES WITH IMETELSTAT-INDUCED TRANSFUSION INDEPENDENCY
Authors: Nicolas Chapuis, David Rombaut, Yannick Simoni, Fei Huang, Michaela Fontenay
Journal: HemaSphere (2023)

Topic: 9. Myelodysplastic syndromes - Biology & Translational Research Background: Myelodysplastic syndrome (MDS), are clonal hematopoietic stem cell disorders characterized by cytopenia and a propensity to leukemic evolution. Maintenance of telomeres, which protects the cells from proliferation arrest and senescence relies on high telomerase activity in cancer cells. Imetelstat, a 13-mer oligonucleotide, specifically binds to template region of the RNA component of human telomerase and acts as a competitive inhibitor of telomerase enzymatic activity. In a phase II clinical trial (NCT02598661), 37% and 23% of 57 highly transfused lower-risk MDS patients achieved an 8-week and 24-week transfusion independency (TI), respectively, with a median TI duration of 65 weeks; 65% obtained a hematological improvement-erythroid. Aims: To identify biological pathways associated with the clinical response, we analyzed bone marrow (BM) mononuclear cell (MNC) transcriptome, peripheral blood (PB) immune cell landscape and plasma cytokines of a subset of patients enrolled in the phase II clinical trial. Methods: Twenty-four BM MNC samples from 10 patients including six 1-year TI responders (TIR) and four 8-wk TI non responders (TINR) at baseline and after 4-7 months, were studied for transcriptomes by RNA sequencing (average depth: 55±5M reads). Gene set enrichment analysis (GSEA) was performed on normalized read counts with gene set permutation test to assess statistical significance. Canonical pathways were determined using Ingenuity Pathway Analysis (IPA) on differentially expressed genes (DEG) with log2FC >|1|and P<0.05. PB MNC immune profile of 6 TIR and 3 TINR were assessed by mass cytometry using a 30-marker MaxPar kit, and data were analysed by both UMAP and manual-gated method. Cytokine profiling using a quantitative multiplex panel of 47 cytokines was performed on plasma samples collected from 21 patients at baseline and up to 4 timepoints post-imetelstat treatment. Results: Baseline transcriptomic analysis identified 1185 DEG (35 up- and 1150 down-regulated in TIR vs TINR). Using GSEA, pathways involved in positive regulation of innate immunity (TLR signaling, NFκB pathway, inflammasome, pyroptosis), type I/II IFN response, T and NK cell-mediated cytotoxicity were downregulated in TIR; using IPA, the TREM1, CREB, and NFκB canonical pathways were downregulated suggesting that innate immunity and inflammation were repressed in TIR. Consistently, baseline levels of proinflammatory IL-18 or CXCL9 chemokine were lower in TIR. Compared to baseline, imetelstat treatment for 4-7 months induced upregulation of pathways involved in T cell activation, B cell proliferation and negative regulation of IL-6 and IL-1β production in TIR. Immune profiling by mass cytometry identified 32 clusters and UMAPs captured the heterogeneity of the samples. At baseline, there was no differences of B, T and NK cell proportions but the proportion of CD4+ effector memory T cells and HLA-DR-CD14+ monocytes was higher in TIR compared to TINR. After 2 cycles of treatment, IL-4, B-cell stimuli IL-5 and IL-27 increased regardless of the response and S100A8/A9 heterodimer decreased in TIR. After 4-7 months of treatment, an increase of B cells, CD8+ terminal effector T cells and a decrease in HLA-DR- monocytes was observed in TIR while TINR exhibited an inflammatory signature with increased TNFα concentrations and decreased anti-inflammatory IL-1RA. Conclusion: Low inflammatory features at baseline and induction of an adaptive immune profile by imetelstat are associated with the TI response, suggesting that immune cell remodeling could contribute to hematopoietic activity of imetelstat treatment. Keywords: Anemia, Immunomodulation, Telemore inhibitors, Myelodysplastic syndrome